Suppression of circulating IgD+CD27+ memory B cells in infants living in a malaria-endemic region of Kenya

Background: Plasmodium falciparum infection leads to alterations in B cell subset distribution. During infancy, development of peripheral B cell subsets is also occurring. However, it is unknown if infants living a malaria endemic region have alterations in B cell subsets that is independent of an age effect. Methods: To evaluate the impact of exposure to P. falciparum on B cell development in infants, flow cytometry was used to analyse the distribution and phenotypic characteristic of B cell subsets in infant cohorts prospectively followed at 12, 18 and 24 months from two geographically proximate regions in western Kenya with divergent malaria exposure i.e. Kisumu (malaria-endemic, n = 24) and Nandi (unstable malaria transmission, n = 21). Results: There was significantly higher frequency and absolute cell numbers of CD19+ B cells in Kisumu relative to Nandi at 12(p = 0.0440), 18(p = 0.0210) and 24 months (p = 0.0493). No differences were observed between the infants from the two sites in frequencies of naïve B cells (IgD+CD27-) or classical memory B cells (IgD-CD27+). However, immature transitional B cells (CD19+CD10+CD34-) were higher in Kisumu relative to Nandi at all three ages. In contrast, the levels of non-class switched memory B cells (CD19+IgD+CD27+) were significantly lower overall in Kisumu relative to Nandi at significantly at 12 (p = 0.0144), 18 (p = 0.0013) and 24 months (p = 0.0129). Conclusions: These data suggest that infants living in malaria endemic regions have altered B cell subset distribution. Further studies are needed to understand the functional significance of these changes and long-term impact on ability of these infants to develop antibody responses to P. falciparum and heterologous infections

IgM memory B cells: a mouse/human paradox

Humoral memory is maintained by two types of persistent cells, memory B cells and plasma cells, which have different phenotypes and functions. Long-lived plasma cells can survive for a lifespan within a complex niche in the bone marrow and provide continuous protective serum antibody levels. Memory B cells reside in secondary lymphoid organs, where they can be rapidly mobilized upon a new antigenic encounter. Surface IgG has long been taken as a surrogate marker for memory in the mouse. Recently, however, we have brought evidence for a long-lived IgM memory B cell population in the mouse, while we have also argued that, in humans, these same cells are not classical memory B cells but marginal zone (MZ) B cells which, as opposed to their mouse MZ counterpart, recirculate and carry a mutated B cell receptor. In this review, we will discuss these apparently paradoxical results

Heterosubtypic Neutralizing Monoclonal Antibodies Cross-Protective against H5N1 and H1N1 Recovered from Human IgM+ Memory B Cells

Background: The hemagglutinin (HA) glycoprotein is the principal target of protective humoral immune responses to influenza virus infections but such antibody responses only provide efficient protection against a narrow spectrum of HA antigenic variants within a given virus subtype. Avian influenza viruses such as H5N1 are currently panzootic and pose a pandemic threat. These viruses are antigenically diverse and protective strategies need to cross protect against diverse viral clades. Furthermore, there are 16 different HA subtypes and no certainty the next pandemic will be caused by an H5 subtype, thus it is important to develop prophylactic and therapeutic interventions that provide heterosubtypic protection. Methods and Findings: Here we describe a panel of 13 monoclonal antibodies (mAbs) recovered from combinatorial display libraries that were constructed from human IgM+ memory B cells of recent (seasonal) influenza vaccinees. The mAbs have broad heterosubtypic neutralizing activity against antigenically diverse H1, H2, H5, H6, H8 and H9 influenza subtypes. Restriction to variable heavy chain gene IGHV1-69 in the high affinity mAb panel was associated with binding to a conserved hydrophobic pocket in the stem domain of HA. The most potent antibody (CR6261) was protective in mice when given before and after lethal H5N1 or H1N1 challenge. Conclusions: The human monoclonal CR6261 described in this study could be developed for use as a broad spectrum agent for prophylaxis or treatment of human or avian influenza infections without prior strain characterization. Moreover, the CR6261 epitope could be applied in targeted vaccine strategies or in the design of novel antivirals. Finally our approach of screening the IgM+ memory repertoire could be applied to identify conserved and functionally relevant targets on other rapidly evolving pathogens

Assessment of splenic function

Hyposplenic patients are at risk of overwhelming post-splenectomy infection (OPSI), which carries mortality of up to 70%. Therefore, preventive measures are warranted. However, patients with diminished splenic function are difficult to identify. In this review we discuss immunological, haematological and scintigraphic parameters that can be used to measure splenic function. IgM memory B cells are a potential parameter for assessing splenic function; however, more studies are necessary for its validation. Detection of Howell–Jolly bodies does not reflect splenic function accurately, whereas determining the percentage of pitted erythrocytes is a well-evaluated method and seems a good first-line investigation for assessing splenic function. When assessing spleen function, 99mTc-labelled, heat-altered, autologous erythrocyte scintigraphy with multimodality single photon emission computed tomography (SPECT)-CT technology is the best approach, as all facets of splenic function are evaluated. In conclusion, although scintigraphic methods are most reliable, they are not suitable for screening large populations. We therefore recommend using the percentage of pitted erythrocytes, albeit suboptimal, as a first-line investigation and subsequently confirming abnormal readings by means of scintigraphy. More studies evaluating the value of potentially new markers are needed

A distinct role for B1b lymphocytes in T cell-independent immunity

Pathogenesis of infectious disease is not only determined by the virulence of the microbe but also by the immune status of the host. Vaccination is the most effective means to control infectious diseases. A hallmark of the adaptive immune system is the generation of B cell memory, which provides a long-lasting protective antibody response that is central to the concept of vaccination. Recent studies revealed a distinct function for B1b lymphocytes, a minor subset of mature B cells that closely resembles that of memory B cells in a number of aspects. In contrast to the development of conventional B cell memory, which requires the formation of germinal centers and T cells, the development of B1b cell-mediated long-lasting antibody responses occurs independent of T cell help. T cell-independent (TI) antigens are important virulence factors expressed by a number of bacterial pathogens, including those associated with biological threats. TI antigens cannot be processed and presented to T cells and therefore are known to possess restricted T cell-dependent (TD) immunogenicity. Nevertheless, specific recognition of TI antigens by B1b cells and the highly protective antibody responses mounted by them clearly indicate a crucial role for this subset of B cells. Understanding the mechanisms of long-term immunity conferred by B1b cells may lead to improved vaccine efficacy for a variety of TI antigens

FcγRIIb differentially regulates pre-immune and germinal center B cell tolerance in mouse and human.

Several tolerance “checkpoints” exist throughout B cell development to control autoreactive B cells and prevent the generation of pathogenic autoantibodies. FcγRIIb is an Fc receptor that inhibits B cell activation and, if defective, is associated with autoimmune disease. Its impact on specific B cell tolerance checkpoints is unknown. Here we show that reduced expression of FcγRIIb leads to increased deletion and anergy of autoreactive immature B cells, but despite this autoreactive B cells expand in the germinal center and serum autoantibodies are produced, even in response to exogenous non-self antigen. Thus, we show FcγRIIb has opposing effects on pre- and post-immune tolerance checkpoints, and suggest B cell tolerance requires the control of “bystander” germinal center B cells with low or no affinity for the immunization antigen.This work was funded by the Wellcome Trust (Programme Grant Number 083650/Z/07/Z to KGCS) and supported by the NIHR Cambridge Biomedical Research Centre. ME was funded by the Wellcome Trust (Programme Grant Number 083650/Z/07/Z), by a Junior Team Leader starting grant from the Laboratory of Excellence in Research on Medication and Innovative Therapeutics (LabEx LERMIT) supported by a grant from ANR (ANR-10-LABX-33) under the program “Investissements d'Avenir” (ANR-11-IDEX-0003-01) and by an ANR @RAction starting grant (ANR-14-ACHN- 0008). KGCS is an NIHR Senior Clinical Investigator and a Distinguished Innovator of the Lupus Research Institute

Snow accumulation and compaction derived from GPR data near Ross Island, Antarctica

We present an improved method for estimating accumulation and compaction rates of dry snow in Antarctica with ground penetrating radar (GPR). Using an estimate of the emitted waveform from direct measurements, we apply deterministic deconvolution via the Fourier domain to GPR data with a nominal frequency of 500 MHz. This reveals unambiguous reflection horizons which can be observed in repeat measurements made one year apart. At two measurement sites near Scott Base, Antarctica, we extrapolate point measurements of average accumulation from snow pits and firn cores to a larger area by identifying a dateable dust layer horizon in the radargrams. Over an 800 m × 800 m area on the McMurdo Ice Shelf (77°45´ S, 167°17´ E) the average accumulation is found to be 269 ± 9 kg m<sup>−2</sup> a<sup>−1</sup>. The accumulation over an area of 400 m × 400 m on Ross Island (77°40´ S, 167°11´ E, 350 m a.s.l.) is found to be higher (404 ± 22 kg m<sup>−2</sup> a<sup>−1</sup>) and shows increased variability related to undulating terrain. Compaction of snow between 2 m and 13 m depth is estimated at both sites by tracking several internal reflection horizons along the radar profiles and calculating the average change in separation of horizon pairs from one year to the next. The derived compaction rates range from 7 cm m<sup>−1</sup> at a depth of 2 m, down to no measurable compaction at 13 m depth, and are similar to published values from point measurements